2.1 Bladder Cancer
Bladder cancer is the most common malignant tumor of the urinary tract and the sixth most common cancer in the United States, excluding non-melanoma skin cancers. Bladder cancer is more common in men than in women. The American Cancer Society estimates that in 2002 there were about 56,500 new cases of bladder cancer diagnosed in the United States (about 41,500 men and 15,000 women). Bladder cancer accounts for 2% of all cancer deaths in the United States, with 8,600 men and 4,000 women (2:1 ratio) dying from bladder cancer in 2002. Most bladder cancers are found on the lateral and posterior walls of the bladder as well as the trigone area. The highest incidence rates for bladder cancer are found in industrialized countries such as the United States, Canada, France, Denmark, Italy, and Spain. The lowest rates are in Asia and South America, where the incidence is only about 30% as high as in the United States.
As with most other cancers, the exact cause of bladder cancer is uncertain. However, several factors may contribute to the development of bladder cancer. The greatest risk factor is tobacco use. Cigarette smoking has been shown to increase the risk of developing bladder cancer up to five times that of non-smokers. As many as 50% of all bladder cancer in men and 30% in women may be attributable to cigarette smoke. Studies show that one in four cases of bladder cancer can be attributed to occupational exposure to known carcinogens such as arylamines. Aniline dye used in the textile, rubber, and cable industries has been identified as an etiologic factor. Beta-naphthylamine, 4-amino-diphenyl, and tobacco tar have been shown to cause tumors in animals. Women who received radiation therapy for the treatment of cervical cancer have an increased risk of developing transitional cell bladder cancer, as do some people who received the chemotherapy drug, cyclophosphamide (Cytoxan).
Gross hematuria, or blood in the urine, is the most common clinical finding and the first sign of bladder cancer in approximately 75% of patients. Sometimes blood clots can form and cause pain or obstruction to the flow of urine. Frequently, bladder irritability and dysuria occur in about one third of patients and increase in the later stages of the disease. Other symptoms associated with bladder cancer include urinary urgency, urinary frequency, painful urinary, urinary incontinence, bone pain or tenderness, abdominal pain, anemia, weight loss, and lethargy. However, a majority of these signs are nonspecific and also associated with other diseases. Diagnostic tests that may be performed include urinalysis, urine cytology (microscopic exam of urine to look for cancerous cells), cystoscopy (use of lighted instrument to view inside of bladder), bladder biopsy (usually performed during cystoscopy), and intravenous pyelogram (IVP) (to evaluate upper urinary tract for tumors or blockage).
There are many different types of bladder cancer. The three main types of cancers that affect the bladder are urothelial carcinoma (also known as transitional cell carcinoma or TCC), squamous cell carcinoma, and adenocarcinoma. These same types of cancer can also develop in the lining of the kidney (called the renal pelvis), the ureters, and the urethra. In fact, it is not unusual for patients with bladder cancer to have a similar type of cancer in the lining of the kidneys, ureters, or urethra. Urothelial carcinoma (with the sub-types papillomas and flat urothelial carcinomas) is by far the most common form of bladder cancer, accounting for more than 90% of these cancers. On the other hand, squamous cell carcinomas account for only about 3% to 8% of bladder cancers. Under a microscope, the cells look much like cells from skin cancers. Nearly all squamous cell carcinomas are invasive. Adenocarcinomas account for only about 1% to 2% of bladder cancers. The cells have a lot in common with gland-forming cells of intestinal cancers. Nearly all adenocarcinomas of the bladder are invasive. Another rare type of bladder cancer is rhabdomyosarcoma.
The staging of bladder cancer is based on the revised criteria of TNM staging by the American Joint Committee for Cancer (AJCC) published in 1988. Staging is the process of describing the extent to which cancer has spread from the site of its origin. It is used to assess a patient's prognosis and to determine the choice of therapy. The stage of a cancer is determined by the size and location in the body of the primary tumor, and whether it has spread to other areas of the body. Staging involves using the letters T, N and M to assess tumors by the size of the primary tumor (T); the degree to which regional lymph nodes (N) are involved; and the absence or presence of distant metastases (M)—cancer that has spread from the original (primary) tumor to distant organs or distant lymph nodes. Each of these categories is further classified with a number 1 through 4 to give the total stage. Once the T, N and M are determined, a “stage” of I, II, III or IV is assigned. Stage I cancers are small, localized and usually curable. Stage II and III cancers typically are locally advanced and/or have spread to local lymph nodes. Stage IV cancers usually are metastatic (have spread to distant parts of the body) and generally are considered inoperable.
Bladder cancer can be treated with surgery, radiation therapy, chemotherapy, surveillance, adjuvant (additional), or a combination of these treatments. Treatment of bladder cancer depends on the type of cancer, the stage, the size and shape of the tumor, the age and general health of the patient.
Surgery is the most common treatment for bladder cancer, although it may not be appropriate for every patient with this type of tumor. Surgical options include transurethral resection (a cystoscope is inserted into the bladder through the urethra), segmental cystectomy (taking out the part of the bladder where the cancer is found), cystectomy (taking out the bladder), and radical cystectomy (taking out the bladder and the tissue around it). In women, the uterus, ovaries, fallopian tubes, part of the vagina, and urethra are also removed. In men, the prostate and the glands that produce fluid that is part of the semen (seminal vesicles) are also removed, and the urethra may be removed as well. The lymph nodes in the pelvis may also be taken out (pelvic lymph node dissection). Urinary diversion is an operation to make a way for urine to pass out of the body so that it does not go through the bladder. It is used to relieve bladder symptoms when the tumor has spread. Further, when the bladder is removed, a procedure called ostomy or urostomy is performed so part of the small intestine is used to make a tube through which urine can pass out of the body through an opening (stoma) on the outside of the body. However, because the risk of recurrence is so high (70% to 100%), people with bladder cancer require constant follow-up for the rest of their lives.
Radiation has not been highly effective as the primary treatment for bladder cancer, though it has been used as palliative therapy for patients with stage IV bladder cancer in an effort to relieve symptoms caused by the tumor. In addition, it has been on patients without metastasis following surgical removal of the primary tumor within the bladder when the surgical margins are positive for tumor involvement, or if there is known residual tumor following surgery. Radiation is also used to shrink an especially large tumor prior to surgery or to slow the growth of inoperable tumors using either external beam (similar to an x-ray) or brachytherapy (internal radiation delivered with implanted radioactive seeds). It is common for the skin in the treated area to become red, dry, tender, and itchy. Radiation to the bladder and nearby areas may cause nausea, vomiting, diarrhea, or urinary discomfort. It may also cause a decrease in the number of white blood cells, cells that help protect the body against infection.
Many types of chemotherapy medications have been used for bladder cancer in various combinations in the past but renal cell carcinoma is highly resistant to chemotherapy. Potential side effects include nausea and vomiting, loss of hair, low blood cell counts, and fatigue. Many chemotherapeutic drugs have been tried in the past as single agents for the palliation of bladder cancer, but the results were generally disappointing. Nevertheless, the role of chemotherapy in the management of bladder cancer is continually evolving. Oftentimes, chemotherapy with radiation in adjunct to surgery is used. In general, chemotherapy can achieve long-term survival rates of up to 15% to 20%, even in patients with recurrent or metastatic disease (Ali et al., 2000, Oncology 14(8):1223–30). Unfortunately, the high initial response rates to first line chemotherapy does not appear to translate into a survival benefit (Kohno and Kitahara, 2001, Gan To Kagaku Ryoho 28(4):448–53). Moreover, there are many undesirable side effects associated with chemotherapy such as temporary hair loss, mouth sores, anemia (decreased numbers of red blood cells that may cause fatigue, dizziness, and shortness of breath), leukopenia (decreased numbers of white blood cells that may lower resistance to infection), thrombocytopenia (decreased numbers of platelets that may lead to easy bleeding or bruising), and gastrointestinal symptoms like nausea, vomiting, and diarrhea. Active chemotherapeutic agents include vinblastine, valrubicin (Valstar™), thiotepa (Thioplex®), mitomycin, and doxorubicin (Rubex®).
The identification of active chemotherapeutic agents against cancers traditionally involved the use of various animal models of cancer. The mouse has been one of the most informative and productive experimental system for studying carcinogenesis (Sills et al., 2001, Toxicol Letters 120:187–198), cancer therapy (Malkinson, 2001, Lung Cancer 32(3):265–279; Hoffman R M., 1999, Invest New Drugs 17(4):343–359), and cancer chemoprevention (Yun, 1999, Annals NY Acad Sci. 889:157–192). Cancer research started with transplanted tumors in animals which provided reproducible and controllable materials for investigation. Pieces of primary animal tumors, cell suspensions made from these tumors, and immortal cell lines established from these tumor cells propagate when transplanted to animals of the same species.
To transplant human cancer to an animal and to prevent its destruction by rejection, the immune system of the animal are compromised. While originally accomplished by irradiation, thymectomy, and application of steroids to eliminate acquired immunity, nude mice that are athymic congenitally have been used as recipients of a variety of human tumors (Rygaard, 1983, in 13th International Cancer Congress Part C, Biology of Cancer (2), pp37–44, Alan R. Liss, Inc., NY; Fergusson and Smith, 1987, Thorax, 42:753–758). While the athymic nude mouse model provides useful models to study a large number of human tumors in vivo, it does not develop spontaneous metastases and are not suitable for all types of tumors. Next, the severe combined immunodeficient (SCID) mice is developed in which the acquired immune system is completely disabled by a genetic mutation. Human lung cancer was first used to demonstrate the successful engraftment of a human cancer in the SCID mouse model (Reddy S., 1987, Cancer Res. 47(9):2456–2460). Subsequently, the SCID mouse model have been shown to allow disseminated metastatic growths for a number of human tumors, particularly hematologic disorders and malignant melanoma (Mueller and Reisfeld, 1991, Cancer Metastasis Rev. 10(3): 193–200; Bankert et al., 2001, Trends Immunol. 22:386–393). With the recent advent of transgenic technology, the mouse genome has become the primary mammalian genetic model for the study of cancer (Resor et al., 2001, Human Molec Genet. 10:669–675).
While surgery, chemotherapeutic agents and radiation are useful in the treatment of bladder cancer, there is a continued need to find better treatment modalities and approaches to manage the disease that are more effective and less toxic, especially when clinical oncologists are giving increased attention to the quality of life of cancer patients. The present invention provides an alternative approach to cancer therapy and management of the disease by using an oral composition comprising yeasts.
2.2 Yeast-Based Compositions
Yeasts and components thereof have been developed to be used as dietary supplement or pharmaceuticals. However, none of the prior methods uses yeast cells which have been cultured in an electromagnetic field to produce a product that has an anti-cancer effect. The following are some examples of prior uses of yeast cells and components thereof:
U.S. Pat. No. 6,197,295 discloses a selenium-enriched dried yeast product which can be used as dietary supplement. The yeast strain Saccharomyces boulardii sequela PY 31 (ATCC 74366) is cultured in the presence of selenium salts and contains 300 to about 6,000 ppm intracellular selenium. Methods for reducing tumor cell growth by administration of the selenium yeast product in combination with chemotherapeutic agents is also disclosed.
U.S. Pat. No. 6,143,731 discloses a dietary additive containing whole β-glucans derived from yeast, which when administered to animals and humans, provide a source of fiber in the diet, a fecal bulking agent, a source of short chain fatty acids, reduce cholesterol and LDL, and raises HDL levels.
U.S. Pat. No. 5,504,079 discloses a method of stimulating an immune response in a subject utilizing modified yeast glucans which have enhanced immunobiologic activity. The modified glucans are prepared from the cell wall of Saccharomyces yeasts, and can be administered in a variety of routes including, for example, the oral, intravenous, subcutaneous, topical, and intranasal route.
U.S. Pat. No. 4,348,483 discloses a process for preparing a chromium yeast product which has a high intracellular chromium content. The process comprises allowing the yeast cells to absorb chromium under a controlled acidic pH and, thereafter inducing the yeast cells to grow by adding nutrients. The yeast cells are dried and used as a dietary supplement.
Citation of documents herein is not intended as an admission that any of the documents cited herein is pertinent prior art, or an admission that the cited documents are considered material to the patentability of the claims of the present application. All statements as to the date or representations as to the contents of these documents are based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.